Notch expression and bevacizumab efficacy in colorectal cancer patients

Background: Antiangiogenic therapies represent a well established additional treatment to standard chemotherapy, nevertheless no markers are available to suggest a successful outcome linked to the use of bevacizumab. To investigate potential mechanisms of resistance to angiogenesis inhibitor bevacizumab, Notch expression was correlated with response and survival in a series of bevacizumab treated advanced colorectal cancer (CRC) patients. Methods: Notch expression was evaluated by immunohistochemistry (IHC) on 65 primary CRC enrolled within 6 randomized clinical trials assessing first-line bevacizumab plus chemotherapy. Notch IHC was conducted using a polyclonal antibody to Cleaved Notch1 (Cell Signaling Technology, Danvers, MA). Notch expression was scored based on intensity of staining (0: none, 1+: weak, 2+: moderate; 3+: strong) and on percentage of immunostained cells. A control series of 21 advanced CRC treated with chemotherapy alone was also examined. Results: Notch positivity was localized to the cytoplasm or nucleus of malignant epithelial cells. In all, 11 of 61 (18%) evaluable primary tumours had a high Notch expression (IHC 3+). Six of the 11 cases (55%) with high Notch expression (IHC 3+) experienced progressive disease compared with 5 of 50 (10%) low Notch expression cases (IHC 0 1+ 2+) (p = 0.003). A high Notch expression also demonstrated an inferior median PFS (4.9 vs. 12.1 months; HR = 2.51; 95% CI, 0.96 to 6.58; p = 0.007) and OS (19.3 vs. 30.4 months; HR = 2.21; 95% CI, 0.79 to 6.15; p = 0.039) compared with low Notch expression cases. When the groups were further analyzed considering VEGF expression, the best outcome was found in low Notch (IHC 0 1 +) and high VEGF expressing tumors (IHC 2+ 3+) (response rate 9 of 11, 82 % vs. 1 of 5, 20%, in patients with high levels of Notch and VEGF expression, respectively). No correlation was found between Notch expression and clinical response in the series of patients treated with chemotherapy without bevacizumab. Conclusions: Notwithstanding the limited power of the present analysis, these data seem to suggest that low Notch expression might be a marker for successful bevacizumab treatment

Strong Notch activation hinders bevacizumab efficacy in advanced colorectal cancer

Aim: To assess the role of Notch activation in predicting bevacizumab efficacy in colorectal cancer (CRC). Materials & methods: Notch activation was evaluated by immunohistochemistry (IHC) on 65 CRC enrolled within randomized clinical trials assessing first-line bevacizumab-based chemotherapy and on 21 CRC treated with chemotherapy alone. Results: Strong Notch (IHC 3+) activation was negatively associated with response (18 vs 62% in low Notch cases [IHC 0, 1, 2+]; p = 0.016), progression-free survival (4.9 vs 12.1 months; p = 0.002) and overall survival (19.3 vs 30.4 months; p = 0.039). No correlation was found between Notch activation and clinical outcome in CRC treated with chemotherapy alone. Conclusion: A potential role of Notch activation in the antitumor activity of bevacizumab could be hypothesized